Proline derivatives and the use thereof as drugs

Abstract

The present invention aims at providing compounds having therapeutic effects due to a DPP-IV inhibitory action, and satisfactory as pharmaceutical products. The present inventors have found that derivatives having a substituent introduced into the γ-position of proline represented by the formula (I) wherein each symbol is as defined in the specification, have a potent DPP-IV inhibitory activity, and completed the present invention by increasing the stability.

1. An L-proline derivative of the formula (I) 
                 
 
       wherein
 X is —NR 1 R 2  wherein R 1  and R 2  may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl, or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring, 
 —NR 3 COR 4  wherein R 3  and R 4  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl,  
 —NR 5 CONR 6 R 7  or —NR 5 CH 2 CH 2 NR 6 R 7  wherein R 5 , R 6  and R 7  are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R 6  and R 7  may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents,  
 —NR 8 SO 2 R 9  wherein R 8  and R 9  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or  
 —OR 10  or —OCOR 11  wherein R 10  and R 11  are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl,  
 
 Y is CH 2 , CH—OH, S, S═O or SO 2 ,  
 Z is a hydrogen atom or a cyano, and  
 
       of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents, or a pharmaceutically acceptable salt thereof. 
     
     
       2. The L-proline derivative of  claim 1 , wherein X of the formula (I) is a group of the formula (II): 
                 
 
       wherein
    is a single bond or a double bond,  
 R 12  is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, —NR 14 R 15 , —OR 16 , —COR 17 , —CO 2 R 18 , —CONR 19 R 20  or —SO 2 R 21  wherein R 14 R 15 , R 16 , R 17 , R 18 , R 19 , R 20  and R 21  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or haloalkyl, or R 14  and R 15 , and R 19  and R 20  may be bonded to each other to form heterocycles each optionally containing 1 or 2 nitrogen atoms or oxygen atoms, said heterocycle optionally being condensed with an aromatic ring optionally having substituents,  
 m is 1 or 2, and  
 A is a carbon atom or a nitrogen atom,  
 
       provided that i) when A is a carbon atom, A may be substituted by a hydroxyl group, carboxyl or alkoxycarbonyl, and ii) when A is a nitrogen atom,
    is a single bond,  
 of the above-mentioned groups, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and heterocycle each optionally have substituents, or a pharmaceutically acceptable salt thereof.  
 
     
     
       3. The L-proline derivative of  claim 1 , wherein X of the formula (I) is a group of the formula (VI) or (VII): 
                 
 
       wherein
 R 23  and R 24  are the same or different and each is independently a hydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halogen, haloalkyl, cyano, nitro, —NR 25 R 26 , —NHSO 2 R 27 , —OR 28 , —COOR 29 , —CONHSO 2 R 30 , —SO 2 OR 31 , —SO 2 R 32  or —CONR 33 R 34  wherein R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33  and R 34  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or haloalkyl, or R 25  and R 26 , and R 33  and R 34  may be bonded to each other to form heterocycles each optionally containing 1 or 2 nitrogen atoms or oxygen atoms, said heterocycle optionally being condensed with an aromatic ring optionally having substituents,  
 a, b, c, d, e, f and g are all carbon atoms, or any one or two thereof is(are) nitrogen atom(s) and the rest is a carbon atom, and  
 A is a carbon atom or a nitrogen atom, provided that when A is a carbon atom, A may be substituted by a hydroxyl group, carboxyl or alkoxycarbonyl, and  
 of the above-mentioned groups, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
       4. The L-proline derivative of  claim 3 , wherein, in the formula (I), the asymmetric carbon, to which X is bonded, is expressed by an S configuration, X is a group of the formula (VI) or (VII), R 23  and R 24  are the same or different and each is nitro, cyano, C 1-6 alkyl, C 1-6 alkyloxy, halogen or haloalkyl, Y is a sulfur atom and Z is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 
     
     
       5. The L-proline derivative of  claim 1 , which is  3 -{(2S,4S)-4-[4-(3-methyl-1-phenyl-5-pyrazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine trihydrochloride. 
     
     
       6. 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-5-pyrazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine or a salt thereof. 
     
     
       7. A pharmaceutical composition containing the L-proline derivative of any one of  claims 1  to  4  or a pharmaceutically acceptable salt thereof, or the L-proline derivative of  claim 5  or a pharmaceutically acceptable salt thereof, or the compound of  claim 6 , and a pharmacologically acceptable carrier. 
     
     
       8. A method for treating diabetes or obesity, which comprises administering to a mammal in need thereof a therapeutically effective amount of the L-proline derivative according to any one of  claims 1  to  4  or  5  or  6 , or a pharmaceutically acceptable salt thereof.